We have developed a model of autoimmune renal disease (RTD) in guinea pigs that has led to the discovery of a similar, previously unrecognized, form of renal disease in man. The hallmark of experimental RTD is the presence of anti-tubular basement membrane (TBM) autoantibodies along the TBM of the proximal tubules and infiltration of mononuclear cells. Because of the relevance of experimental RTD to human nephritis, and immunologic tissue injury in general, we are studying this pathogenesis to determine the mechanism by which mononuclear cells accumulate in the target tissue. At present our observations point toward a new type of inflammatory response which involves autoantibodies, complement, radiosensitive mononuclear cells as well as radioresistant macrophages. Delayed hypersensitivity has been largely ruled out as a possible mechanism. Lesions can be induced by passive transfer of serum antibodies but not by sensitized cells; furthermore, we found that nitridazole, a potent inhibitor of cell-mediated immunity, does not inhibit the passive transfer whereas complement depletion by cobra venom factor does. We further characterized the nature of the cellular infiltrate and the mediators which account for the lymphocyte-macrophage accumulation. Our observations suggest a new hypothesis for the inflammation in this model: Unsensitized B-lymphocytes are activated by C3 in the target tissue; such cells release factors that account for the accumulation of macrophages. During these studies we performed allogeneic bone marrow transplants and found that C4 deficient guinea pigs can be reconstituted with normal bone marrow. Other studies are in progress on the bio-synthesis of complement components to determine the as yet unexplained rise of C1 synthesis in the radiation chimeras. BIBLIOGRAPHIC REFERENCES: Rudofsky, U.H. and Pollara, B.: Studies on the pathogenesis of experimental autoimmune renal tubulointerstitial disease in guinea pigs. 2. Passive transfer of renal lesions to leukocyte-depleted recipients by antitubular basement membrane auto-antibodies and non-immune bone marrow cells. Clin. Immunol. Immunopathol., 6: 107, 1976. Rudofsky, U.H.: Studies on the pathogenesis of experimental autoimmune renal tubulointerstitial disease in guinea pigs. 3. The role of adjuvants in the induction of disease. Clin. Exp. Immunol., 25: 455, 1976.